2) ...even though the molecular differences in the mutant dystrophin gene are known in great detail.
3) It would be a giant step forward to invent some way to avoid mechanical killing of DMD muscle cells.
4) But it isn't known exactly why lack of normal dystrophin proteins causes death of muscle cells.
5) Women who are "carriers", heterozygous for the mutation that causes Duchenne muscular dystrophy, have only mild, barely detectable symptoms, do not become paralyzed, and are not caused to die young.
6) Dosage compensation in mammals works by random inactivation of transcription of all genes on one or the other of the two X chromosomes in females.
7) Because skeletal muscle cells have many nuclei per cell, and also because they become multi-nucleate by fusion of uninucleated myoblasts, in the skeletal muscles of women heterozygotes (carriers) about half their nuclei transcribe mRNA for the normal dystrophin protein and the other half of their nuclei transcribe mRNA for the abnormal, short, incomplete, carboxy-terminal end of this protein - the form of dystrophin that causes muscular dystrophy.
8) The combination of #6 and #7 mean that skeletal muscle cells can survive OK with only half the usual amount of the normal form of the dystrophin protein, and also that they are not harmed by having about that same amount of the abnormal form of the protein (that would cause DMD if homozygous or hemizygous).
9) In addition, those uni-nucleate cell types (including cardiac and smooth muscle cells, nerve cells and Schwann cells), all of which normally contain dystrophin, must somehow not be killed or seriously harmed by containing only the form of dystrophin that causes the serious paralysis and fatal disease in males. (Or else half of these cells would die in women "carriers", heterozygous for the mutant gene).
10) "Dystrophic" mouse skeletal muscle cells have been discovered to resist surface denting by microneedles with only one fourth the normal force.
11) The normal function of dystrophin is mechanically linking actin fibers to the plasma membrane.
12) We need to figure out why weakening this mechanical linkage gradually causes death of more and more skeletal muscle cells in males who are hemizygous for the DMD version of the gene.
13) One possibility is that contraction of the sarcomeres pulls the acto-myosin fibers loose from the costameres of the plasma membranes.
14) Another possibility is that either osmotic pressure, or ordinary water pressure produced by shortening of muscle cells, pushes the plasma membrane outward away from its attachments to the cytoskeleton.
15) Researchers should consider the possibility that "The Danowski Phenomenon" (stimulation of increased polymerization of actin and myosin by even low doses of anti-microtubule drugs) could be used to treat muscular dystrophy patients with low doses of colchicine, vinblastine, or nocodazole. The first two of these drugs have long been used to treat gout and cancer, respectively.
16) Longer-term time-lapse observations should be made of dystrophic skeletal muscle cells and cardiac muscle cells, spread on thin layers of silicone rubber, to find out if force exertion is abnormal.
17) Effects of osmotically hypo-osmotic tissue culture media should be studied on dystrophic cardiac muscle and cardiac muscle cells.
18) Low doses of colchicine, etc. should be tried to see if they help protect muscle cells from dying.
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